Esophageal eosinophilia has a strong association with T helper type 2 (Th2) allergic responses and occurs in a variety of states including eosinophilic esophagitis (EE). Recently, we made a novel observation that local induction of Th2 cytokines, eosinophils and T cells are critical in the pathogenesis of EE. Despite these efforts and findings, we are still unable to target specific cell types, chemokine or cytokine for therapeutic intervention strategy for the treatment of EE. In order to further provide insight into the molecular and cellular mechanisms of EE pathogenesis, we now focus our attention to investigate the role of IL-15 and iNKT cells in EE pathogenesis. The rationale behind understanding their role in EE is, i) IL-15 and iNKT cell associated genes are induced in both experimental and human EE;ii) IL-15 is produced by a number of inflammatory cells including dendritic cells and epithelial cells;iii) IL-15 is required for the development of naove and memory CD8 T cells, intestinal intraepithelial lymphocytes (IEL), NK and iNKT cell lineages;and iv) IL-15 and iNKT cells are implicated in a broad range of autoimmune and allergic diseases but has not previously been studies in EE. In this grant proposal, the PI proposes to test the hypothesis that the pathogenesis of EE involves IL-15-induced iNKT cell-mediated inflammation. We propose three aims designed to test the role of IL-15 in experimental and human EE. In the first aim, we will examine the critical role of IL-15 in the induction of EE. The second aim will be focused on the mechanism of iNKT cell esophageal homing, activation, and the role in EE pathogenesis. In the third aim, we will translate our pre-clinical observations into the human EE by examining the levels of IL-15, iNKT cells and their related homing and activation molecules in normal individuals and EE patients, and analyzing their correlations with the esophageal eosinophilia. Our studies are timely given the recent attention that EE is receiving in the medical community. Eosinophilic esophagitis (EE) is a worldwide growing medical problem;however, the etiology of the disease pathogenesis is not well understood. The goal of our proposed study is to identify a target molecule for EE therapy by examining the role of IL-15 and iNKT cells in the pathogenesis of EE. PUBLIC HEALTH RELEVANCE: Eosinophilic esophagitis (EE) is a worldwide growing medical problem;however, the etiology of the disease pathogenesis is not well understood. The goal of our proposed study is to identify a target molecule for EE therapy by examining the role of IL-15 and iNKT cells in the pathogenesis of EE.